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J. Biol. Chem., Vol. 276, Issue 20, 17354-17360, May 18, 2001
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From the Department of Pathology, Brigham and Women's Hospital and
Harvard Medical School, Boston, Massachusetts 02115
The estrogen receptor mediates breast cell
proliferation and is the principal target for chemotherapy of breast
carcinoma. Previous studies have demonstrated that the estrogen
receptor binds to calmodulin-Sepharose in vitro. However,
the association of endogenous calmodulin with endogenous estrogen
receptors in intact cells has not been reported, and the function of
the interaction is obscure. Here we demonstrate by
co-immunoprecipitation from MCF-7 human breast epithelial cells that
endogenous estrogen receptors bind to endogenous calmodulin. Estradiol
treatment of the cells had no significant effect on the interaction.
However, incubation of the cells with tamoxifen enhanced by 5-10-fold
the association of calmodulin with the estrogen receptor and increased
the total cellular content of estrogen receptors by 1.5-2-fold. In
contrast, the structurally distinct calmodulin antagonists
trifluoperazine and CGS9343B attenuated the interaction between
calmodulin and the estrogen receptor and dramatically reduced the
number of estrogen receptors in the cell. Neither of these agents
altered the amount of estrogen receptor mRNA, suggesting that
calmodulin stabilizes the protein. This hypothesis is supported by the
observation that, in the presence of Ca2+, calmodulin
protected estrogen receptors from in vitro proteolysis by
trypsin. Furthermore, overexpression of wild type calmodulin, but not a
mutant calmodulin incapable of binding Ca2+, increased the
concentration of estrogen receptors in MCF-7 cells, whereas transient
expression of a calmodulin inhibitor peptide reduced the estrogen
receptor concentration. These data demonstrate that calmodulin binds to
the estrogen receptor in intact cells in a
Ca2+-dependent, but estradiol-independent,
manner, thereby modulating the stability and the steady state level of
estrogen receptors.
Calmodulin Enhances the Stability of the Estrogen Receptor*
, and
*
This work was supported in part by a grant from the National
Institutes of Health (to D. B. S.) and a Breast Cancer Research Grant
from the Massachusetts Department of Public Health (to J. L. J.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Current address: Praecis Pharmaceuticals, Inc., One Hampshire St.,
Cambridge, MA 02139.
§
To whom correspondence should be addressed: Brigham and
Women's Hospital, Thorn 530, 75 Francis St., Boston, MA 02115. Tel.: 617-732-6627; Fax: 617-278-6921; E-mail:
dsacks@rics.bwh.harvard.edu.
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